Intercalation, DNA

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

The AMAPs (2-[ arylmethyl amino]-l,3-propanediols) are a class of planar polycyclic aromatic derivatives, which contain polar side-chains. They are known to be DNA intercalators and possess broad spectrum antitumour activity. An approach to C-radiolabelled AMAP derivative 40 used the Bucherer reaction as an initial starting reaction. 2-Naphthol was reacted with 4-bromophenylhydrazine 38 in the presence of sodium metabisulfite and HCl to afford 39. Subsequent derivatisation of 39 afforded 40. 

The Pictet-Hubert reaction has found utility in the production of phenanthridine molecules that act as DNA-intercalator antitumor and antiviral agents (17). 

Hie reactions of 4-chloropyridines and quinolines 17 with benzotriazoles 18 in a modified Graebe-Ullman synthesis give excellent yields of Y arbolines and their benzo-fused derivatives 20. Excellent yields for preparation of the penultimate benzotriazole precursors 19 are reported as well. In the optimized one-pot conditions, the combined neat substrates are heated with microwave irradiation (MW) for short (7-10 min) durations. The crude 19 is treated with H4P2O7 and irradiated futher (4-6 min). The resultant y-carbolines 20 were methylated to form the quaternary salts. These were tested and found to lack DNA intercalation properties <96JOC5587>. 

The most important aspect of coralyne is its ability to inhibit DNA relaxation in a fashion significantly similar to the most potent antitumour alkaloid camptothecin, which is known to exert this property [242], Presumably, the most notable biological action of these alkaloids appears to be topoisomerase inhibition [238-242], which has direct relevance to their DNA intercalating property. In this context. Pilch et al. [167] described a mixed binding mode model (Fig. 16) in which the protoberberine structure constitutes portions that can intercalate or bind to the minor groove of DNA. Wang et al. [240] demonstrated that coralyne (Ci) and several of its derivatives (Ce to Ch) (Scheme 5), including the partial saturated... 

Multimolecular helical inclusion networks formed by rigid alicyciic diols, urea, deoxycholic acid, and tri-o-thymotide are described and contrasted, followed by discussion of DNA intercalates, amylose compounds, and other inclusion systems formed by helical polymers. 

Zhu, X.Q., Chilton, N.B., Beveridge, I. and Gasser, R.B. (1998a) Detection of sequence variation in parasite ribosomal DNA by electrophoresis in agarose gels supplemented with a DNA-intercalating agent. Electrophoresis 19, 671-674. 

The thienothienopyridines are a relatively little-known class of compound. Interest in these systems arose through the possibility that they occurred in coal-derived products and their extended 7i-systems initiated interest for their interesting optical properties. Additionally, several differently substituted examples have antitumor activity <2002CPB656>, and may serve as DNA intercalating agents <2005MOL279>. 

Indolopyridopyridazinium salts such as 498 can be prepared by treatment of the iV-aminopyridoindolium salt 497 with a 1,2-diketone (Equation 218). These compounds can act as DNA intercalators <1996BML1453, 1999JOC3907>. 

Fig. 8.11 Melting curves obtained for native DNA and DNA intercalated within AMP.

Daunorubicin -anthracycline antitumor antibiotic DNA intercalating agent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -vesicant if extravasated —cardiotoxicity (550 mg/M2) -Liposomal daunorubicin there is significantly less bone marrow suppression, nausea and vomiting, stomatitis, and cardiotoxicity... 

Recent structure-activity studies of 1-alkylbenzo[a]pyrenes also suggest that DNA intercalation of benzo[a]pyrene (BP) metabolites plays a role in the mechanism of BP carcinogenesis (38). The addition of bulky alkyl groups at the 1-position of BP, which inhibit DNA intercalation of 1-alkyl-BP metabolites (19), causes a reduction in carcinogenic activity. 

Intercalation of BPDE. Several groups have studied the reversible intercalative binding of BPDE to DNA. The fluorescence quantum yield of BPDE is much lower than that of BP derivatives which do not contain an epoxide group and fluorescence techniques have not been widely used to study BPDE physical binding to DNA (4). Association constants for the DNA intercalation of BPDE have been obtained by measuring red shifts in the UV absorption spectra of BPDE which occur upon the formation of intercalated complexes and from fluorescence studies (8) of the kinetics of DNA catalyzed hydrolysis of BPDE. The hydrolysis reaction is conveniently monitored by following the fluorescence of the hydrolysis product, BPT, which has a quantum yield many times greater than BPDE. 

Table III. DNA Intercalation Association Constants Reported for trans-7,8-Dihydroxy-ant i-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene...

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